Role of the Follicle-Depleted Ovary in the Pathogenesis of Chronic Diseases

描述(申请人提供)：全球绝经后妇女人口正在增加(预计到2025年将达到11亿)，这些妇女比她们的前辈活得更长。冠心病(CHD)、骨质疏松症和代谢综合征构成了影响这一人群的健康负担的很大部分。然而，尽管进行了大量的流行病学和临床研究，但这些慢性和退行性疾病的起始和发展轨迹仍不清楚。认识上的两个具体差距是：1)围绝经期是否或在多大程度上是疾病加速发展的时期；2)绝经时积累的病理生物学变化是否确立了绝经后疾病结局的轨迹。因此，这项申请寻求支持，以继续研究围绝经期和绝经期后的猴子。这项正在进行的研究利用了我们研究所最近开发的绝经转变的非人类灵长类动物模型。这个模型是从围绝经期小鼠的模型改编而来的，后者使用一种化学物质(4-乙烯基环己烯二环氧化物-VCD)通过细胞凋亡和闭锁来破坏原始卵泡。该模型概括了妇女在围绝经期过渡期间所经历的生理变化，包括原始卵泡数量减少和最终枯竭，以及随后抗髓质激素(AMH)的减少。此外，导致卵泡耗尽的卵巢间质具有与自然绝经后妇女相似的生物学活性(例如，雄激素产生)。综上所述，与卵巢切除动物相比，该模型有几个优势，卵巢切除动物是一个研究平台，不会产生与自然绝经后妇女观察到的激素特征或风险因素(如血清血脂)相媲美的研究平台。关于围绝经期过渡和绝经后的现有知识空白促使我们提出以下四个具体目标：1)确定直接通过活检测量的饮食导致动脉粥样硬化进展的程度，在去卵巢(OVX)、围绝经期(VCD治疗)和绝经前猴子中不同，是否围绝经期动脉粥样硬化程度决定绝经后动脉粥样硬化的发展程度，最后，动脉粥样硬化进展的轨迹在围绝经期和绝经后阶段是否不同；2)确定在围绝经期过渡期间是否发生骨丢失，并将确实发生的任何骨丢失的程度与在绝经后阶段观察到的骨丢失程度进行比较；3)确定代谢综合征的元素在围绝经期过渡期间是否出现以及在多大程度上出现，以及在围绝经期或绝经后阶段增加更大；以及4)比较和对比在围绝经期和绝经后接受VCD治疗的猴子的激素特征，以及在这些生殖阶段观察到的卵巢激素的变化是否与动脉粥样硬化程度以及心血管、骨骼和代谢风险生物标志物的变化有关。公共卫生相关性：通过这项调查获得的信息将为妇女及其医生提供迫切需要的证据，以便根据这些证据作出关于围绝经期和绝经后治疗选择的决定。此外，这项研究中观察到的结果很可能超出血管和肌肉骨骼系统，包括对卵巢激素影响敏感的其他组织，如大脑。

DESCRIPTION (provided by applicant): The worldwide population of postmenopausal women is increasing (expected to be 1.1 billion by 2025) and these women are surviving longer than their predecessors. Coronary heart disease (CHD), osteoporosis, and the metabolic syndrome comprise a substantial part of the health burden affecting this population. However, despite considerable epidemiological and clinical research, the initiation and trajectory of these chronic and degenerative conditions remain unclear. Two specific gaps in knowledge are: 1) whether or to what extent the perimenopause is a time of accelerated disease progression; and 2) whether the pathobiological changes that have accumulated by the time of menopause establish the trajectory of postmenopausal disease outcomes. Accordingly, this application seeks support to continue a study of peri- and post-menopausal monkeys. The study in progress takes advantage of a nonhuman primate model of the menopausal transition developed recently at our institution. This model was adapted from a mouse model of perimenopause which uses a chemical (4-vinylcyclohexene diepoxide -VCD) to destroy primordial follicles via apoptosis and atresia. The model recapitulates the physiological changes experienced by women during the perimenopausal transition, including decreased numbers and ultimate depletion of primordial follicles and subsequent decreases in antimullerian hormone (AMH). Further, the stroma of the resulting follicle-depleted ovary has similar biologic activity (e.g. androgen production) to that of naturally postmenopausal women. As summarized, this model has several advantages over ovariectomized animals, a research platform that does not yield hormonal characteristics or risk factors (e.g., serum lipids) comparable to those observed in naturally postmenopausal women. The existing gaps in knowledge surrounding the perimenopausal transition and postmenopause prompted us to propose the following four Specific Aims: 1) Determine the extent to which diet induced atherosclerosis progression, as measured directly through biopsy, differs among ovariectomized (OVX), perimenopausal (VCD treated) and premenopausal monkeys, whether perimenopausal atherosclerosis extent determines the extent of postmenopausal atherosclerosis development, and finally, whether the trajectories of atherosclerosis progression differ between the peri and postmenopausal phases; 2) Determine whether bone loss occurs during the perimenopausal transition and to compare the magnitude of any bone loss that does occur with that observed during the postmenopausal phase; 3) Determine if and to what extent, elements of the metabolic syndrome appear during the perimenopausal transition, and whether the increases are greater in peri or postmenopausal phase; and 4) To compare and contrast the hormonal characteristics of VCD-treated monkeys both peri- and postmenopausally, with those observed in their OVX and premenopausal counterparts, and to determine whether changes in ovarian hormones in these reproductive phases are associated with changes in atherosclerosis extent and cardiovascular, skeletal, and metabolic risk biomarkers. PUBLIC HEALTH RELEVANCE: The information gained through this investigation will provide women and their physicians with urgently required evidence on which to base decisions concerning peri- and postmenopausal treatment options. In addition, the outcomes observed in this study might well extend beyond the vascular and musculoskeletal systems to include other tissues that are sensitive to the effects of ovarian hormones, such as the brain.